Auditory hallucinations and other positive symptoms of schizophrenia (SCZ) such as delusions, disorganized thought, and psychosis typically appear during late adolescence or early adulthood1,2 and are alleviated in most patients by antipsychotics that inhibit D2 dopamine receptors (DRD2s)3-5. The mechanisms of such late onset of schizophrenia's positive symptoms and underlying neuronal circuits remain unknown. Thalamocortical (TC) projections to the auditory cortex (ACx) emerged as a circuit specifically disrupted in mouse models of 22q11 deletion syndrome (22q11DS)6,7. This disorder is a leading genetic cause of schizophrenia8-10 and instigated by the hemizygous deletion of multiple genes (1.5-3 Mb) of the q (long) arm of chromosome 22 in humans11. Deletion of one 22q11DS gene, the microRNA (miRNA)-processing gene Dgcr8, leads to high levels of Drd2 in the auditory thalamus, TC disruption, abnormal sensitivity of TC projections to antipsychotics, and deficits in acoustic-startle responses characteristic of schizophrenia6, through miRNA depletion12-14.
Several studies have indicated that drug-naïve schizophrenic patients have elevated levels of DRD2s in their brains25,26. Drd2 upregulation leads to deficits in TC synaptic transmission and acoustic startle and also renders TC projections sensitive to antipsychotics. Antipsychotics that effectively treat only positive symptoms but not cognitive or negative symptoms of the disease27, eliminate synaptic deficits at TC projections and acoustic-startle deficiency in 22q11DS mice6. Antipsychotics alleviate positive symptoms of schizophrenia through systemic inhibition of DRD2, which is accompanied by multiple and sometimes devastating side effects, such as blood abnormalities, weight gain, abnormal movements (such as the movements as with Parkinson's disease) and many others2,28.
The 22q11.2 deletion syndrome (22q11DS) is associated with high risk of developing schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical projections recently emerged as a circuit specifically disrupted in 22q11DS mouse models. Haploinsufficiency of the microRNA-processing gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. These auditory abnormalities have a delayed onset in 22q11DS mouse models and are associated with age-dependent reduction of the microRNA miR-338-3p, which targets Drd2 and is enriched in the thalamus of humans and mice. Replenishing depleted miR-338-3p in the mature 22q11DS mice rescued the thalamocortical abnormalities, and miR-338-3p deletion/knockdown mimicked thalamocortical and behavioral deficits and eliminated their age dependence. Thus, miR-338-3p depletion is necessary and sufficient to disrupt auditory thalamocortical signaling in 22q11DS mouse models and may therefore mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.
The 22q11DS is considered a leading genetic cause of schizophrenia46-48. Schizophrenia develops in 23% to 43% of individuals with 22q11DS49-54, most of whom experience psychosis55, 56 Furthermore, 30% to 50% of nonschizophrenic individuals with 22q11DS demonstrate subthreshold symptoms of psychosis57. Nonpsychotic behavioral abnormalities are present from early adulthood in 22q11DS58, 59, but psychotic symptoms and schizophrenia are delayed until adulthood54, 60 It remains unclear why the onset of psychotic symptoms is so delayed. In schizophrenic patients, auditory hallucinations and other psychotic symptoms are similarly delayed until late adolescence or early adulthood61, 62, are present in 60% to 90% of cases63, and are often alleviated by antipsychotics that inhibit D2 dopamine receptors (DRD2s)64-67. Given the germline occurrence of deleted genes in 22q11DS, it is not clear why the onset of positive symptoms is delayed.
Recently, Dgcr8 emerged as a culprit gene responsible for several neuronal phenotypes observed in mouse models of 22q11DS68-70, including the disruption of synaptic transmission at TC projections to the ACx39. Dgcr8 is part of the microprocessor complex that mediates the biogenesis of microRNAs (miRNAs), small RNAs that negatively regulate the expression of complementary mRNAs and protein translation71. Dgcr8 haploinsufficiency in 22q11DS leads to depletion of miRNAs and the resultant upregulation of respective targets, which in turn disrupts synaptic transmission, synaptic plasticity, and proper functioning of neural circuits72. In adult 22q11DS mouse models, Dgcr8 haploinsufficiency is sufficient to upregulate Drd2 mRNA and protein in the auditory thalamus, which causes auditory abnormalities that include decreased glutamatergic synaptic transmission at TC projections to the ACx and deficient prepulse inhibition (PPI) of the acoustic-startle response39. Abnormally high levels of Drd2 in the thalamus of 22q11DS mice increase TC projection sensitivity to Drd2 antagonists, including antipsychotics. As a consequence, auditory synaptic and behavioral abnormalities of 22q11DS mice are rescued by antipsychotics39.
It was tested whether TC disruption follows the same age-dependent trajectory as psychosis in patients with 22q11DS or schizophrenia and determined the molecular underpinnings of TC disruption in 22q11DS mice. Similar to psychotic symptoms, TC disruption of synaptic transmission had a delayed onset. In a series of miRNA and physiological screens, the thalamus-enriched Drd2-targeting miR-338-3p was identified as that which mediates the Dgcr8-Drd2 mechanism of TC disruption. It is also shown that miR-338-3p is depleted in mouse models of 22q11DS and schizophrenic patients and that replenishment of miR-338-3p in the auditory thalamus rescued the TC deficits in 22q11DS mouse models. Lastly, evidence is presented showing that miR-338-3p is a key controller of the late onset of TC disruption in 22q11DS mice.